Fundamentals of Regulatory Affairs, 8th edition
Ch. 14 Patents and Exclusivity
Joan Bergstrom
Henkel Consumer Goods, Inc.
Introduction
• Hatch-Waxman Act of 1984 gave brand-name drug companies
incentives to do new drug research including:
• Patent term extension for time lost during Regulatory review
• Listing patent in Orange Book
• Eligibility for a period of non-patent exclusivity
• Additional incentives created by other laws including:
• Orphan Drug Act – drug development for rare diseases
• Best Pharmaceuticals for Children Act – developing medicine for kids
Patents and Exclusivity
Patents
• Affords right to prevent
competitor from making same
• Granted by the Patent and
Trademark office
• Awarded anytime during
development of a drug
• Usual duration is 17-20 years
Exclusivity
• Affords manufacturer exclusive
marketing rights
• Granted by the FDA
• Awarded upon approval of a
drug (NDA)
• A statutory provision, if
requirements are met
• Duration varies
Patents and Exclusivity
• Patents can be expired before drug approval, issued after drug
approval, and anywhere in between
• Exclusivity is granted upon approval of a drug product if the statutory
requirements are met
• Some drugs have both patent and exclusivity protection while others
have just one or none
• Patents and exclusivity may or may not run concurrently and may or
may not encompass the same claims
• Exclusivity is not added to the patent life
Patent-Related Market Exclusivity
• Patent generally keeps other companies from making same product
for a period of time, protecting the $ investments by patent holder
• Time is lost during regulatory review of a product is an issue
• Regulatory Review Time = Testing Phase Time + Review Phase Time
• Period from submission to approval of NDA
• Hatch-Waxman Act of 1984 says patent term may be extended
• Extension = ½ Testing Phase time + Review Phase time
• Assuming due diligence is maintained!
• Not to exceed 14 years after date of approval of marketing application
Patent Term Extension Law
• Definition: “Drug Product” is active ingredient (AI) of a new drug, and
salts or esters, as a single entity or in combination with other AI
• Law provides that patent for drug may be extended from original
issue date IF:
1.
2.
3.
4.
5.
Term of patent has not expired
Patent not previously been extended
Extension application submitted by owner w/in 60 days of NAD approval
Product in Reg. Review before it is commercially available
NDA is first permitted commercial use of drug product
Orange Book
• Approved Drug Products with Therapeutic Equivalence Evaluations
(commonly known as the Orange Book)
• Lists drug products approved on the basis of safety and effectiveness
by the FDA under the Federal Food, Drug, and Cosmetic Act
• First published in 1980, now electronic database
• Orange Book Data updated Monthly
• Generic Drug Product Information updated Daily
• Patent Information updated Daily
Orange Book Patent Listing
• Patent information is required to be submitted with all new drug
applications at the time of NDA submission
• Patent information is published in the Orange Book after approval of
NDA, upon receipt of FDA form 3542
• For patents issued after approval of the NDA, the applicant holder has
30 days in which to file the patent to have it considered as a timely
filed patent. Patents may still be submitted beyond the 30 day
timeframe, but the patent is not considered a timely filed patent.
• Expired patents and exclusivity are not included in the published list
Non-Patent Statutory Market Exclusivity
Five Year Exclusivity
• 5-year exclusivity granted to sponsor of a drug not previously approved
under NDA, referring to a New Chemical Entity
• Sometimes called “NCE Exclusivity”, prevents approval of a generic equivalent for
5 years
Three Year Exclusivity
• 3-year exclusivity granted to sponsor of a drug previously approved under
NDA, but reports New Clinical Investigations (studies)
• Must be studies essential to approval
• Must be studies conducted by same sponsor
• Called the “NCI Exclusivity” or “New Use Exclusivity”
Non-Patent Statutory Market Exclusivity (cont.)
Pediatric Exclusivity
• Provides an additional 6 months exclusivity to sponsor that conducts
acceptable and beneficial Pediatric Studies
• Submit Pediatric Written Request (PWR) to FDA
• Applies to ALL indications of the drug or formulation, not just pediatric
Orphan Drug Exclusivity
• Grants 7 year exclusivity to sponsor of a drug for a “rare disease or
condition”
• Affects fewer than 200,000 people or sponsor shows inability to recover
development or marketing costs
• Other or subsequent drugs must be “different” or “clinically superior” to be
approved within the 7 years
Duration of Drug Exclusivity
How long is exclusivity granted for?
It depends on what type of exclusivity is granted:
New Chemical (NCE) - 5 years
Orphan Drug (ODE) - 7 years
New Clinical Investigation (NCI) - 3 years, if criteria are met
Pediatric (PED) - 6 months added to existing Patents/Exclusivity
Patent Challenge (PC) – 180 days (this exclusivity is for ANDAs only)
• See 21 C.F.R. 314.108 New Drug Product Exclusivity
Patent Filing
• Leahy-Smith America Invents Act (AIA) of 2011 significantly modified
the patent filing process
• AIA went into effect March 2013
• Grants the patent to the entity “first to file” the application regardless
of any previous publications
• Caused defensive publication planning by many companies
• Requires greater diligence of competitive landscape
Fundamentals of Regulatory Affairs, 8th edition
Ch. 15 Over-the-Counter Drug Products
Joan Bergstrom
Henkel Consumer Goods, Inc.
Introduction
• Over-the-counter (OTC) drugs play increasingly important role
• Durham-Humphrey Amendment to the FD&C Act in 1951 established
three criteria for Prescription status drugs
• Habit forming drugs
• Not safe for use unless supervised by healthcare professional
• Limited to prescription use under NDA
• All drugs that did not meet these criteria = OTC drugs
Regulation of OTC Drugs
• Regulations applicable to Rx drugs also apply to OTC drugs
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•
•
•
All aspects of drug manufacture and testing (GMP’s)
Facility listing and inspections
Drug registrations
Clinical trials and safety oversight
• Both review and approval of OTC drugs done by FDA Center for Drug
Evaluation and Research’s (CDER) office
• Two main avenues to receive approval for an OTC drug
• OTC Monograph route – Safety and efficacy data known, using approved
active ingredients and labeling
• NDA / ANDA route – submit safety and efficacy data
OTC Monograph Route
• In 1972, FDA initiated OTC Drug Review Process
• Encompassed review of safety and efficacy of products on the market
• Started by grouping products into therapeutic categories and evaluating the
active ingredients rather than each product
• FDA now reviews active ingredients and labeling for more than 80
therapeutic classes of drugs (monographs, not all finalized)
• OTC Monograph is developed and published in the Federal Register
OTC Monograph Review Process
• Review of safety and efficacy data done by therapeutic category specific
Advisory Panels, subject matter experts
• Advisory Panel recommended active ingredients be classified as
• Category I – generally regarded as safe and effective, not misbranded
• Category II – not generally regarded as safe and effective, or is misbranded
• Category III – insufficient data to permit classification
• After comment periods, FDA published conclusions as
• Tentative Final Monographs (Proposed Rule)
• Final Monograph (Final Rule)
• No defined timelines to move from TFM to FM, can be lengthy process
• Can market products under TFMs
• FDA can amend FMs as new information is available
NDA Route
• Products not covered by OTC monographs are subject to NDA process
prior to marketing
• Four NDA Routes
• Direct-to-OTC NDA – same requirements as Rx NDA, PLUS demonstration
product can be safely used without healthcare professional supervision
• Rx-to-OTC Switch – used when Rx shows it can be safely used without
healthcare professional supervision
• NDA Monograph Deviation – used when a drug product deviates in any aspect
from the OTC Monograph, like dosage form. NDA submitted with S&E data.
• Generic (ANDA) - same requirements as Rx NDA, with bioequivalence data
OTC NDA Products and Specific Studies
• Manufacturers must conduct Safety, Efficacy, and Preclinical studies
• Additional studies for OTC products:
• Label comprehension – evaluate extent to which a consumer can understand and
apply information on OTC label when making drug product use decisions
• Open label and uncontrolled
• No drug product is used
• Self-selection – evaluate whether consumer makes correct decision on use/no use
based on label information and knowledge of personal medical history
• No drug product used
• Suitable label based on comprehension should be created before test
• Actual use test (AUT) or Simulation Trial – evaluate consumer behavior
• Conducted under an IND
• “all comers” study with actual product
Labeling of OTC Drugs
• Primary responsibility over OTC drug labeling belongs to FDA
• In 1999, “Drug Facts” labeling rule became effective
• Standardized format, content, headings, graphics, and min. type size
• Ensure product information is easy to find and understand when
used by ordinary people
Drug Facts Label
• Regulation 21 CFR 201.66
• Specific information on OTC label:
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•
•
•
•
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Active ingredient
Uses
Warnings
Inactive ingredients
Purpose
Directions
OTC Drug Packaging Requirements
• Tamper evident packaging has become standard
• Regulation 21 CFR 211.132
• Statement on both inner and outer pack show tamper-evident
features
• Must comply with child-resistant package requirements
• Requirements as defined in the Poison Prevention Packaging Act
(PPPA) of 1970
• Consumer Product Safety Commission (CPSC) enforces child-resistant
package requirements
FDA Oversight
• All OTC drug manufacturing activities must comply with 21 CFR 210
and 211
• Drug manufacturing sites are required to register with the FDA
• Subject to prior approval inspections for NDA products and other
routine inspections
• All OTC drug products must be drug listed, though NDC number not
required on OTC drug product label
• Mandated safety reporting per the Dietary Supplement and
Nonprescription Drug Consumer Protection Act of 2006
Assigning a Product Class
• Classified based on intended use as defined by FD&C Act
• Intended use determined by:
• Product claims
• Consumer perception
• Drug ingredients
ex. Cleans
ex. Fluoride
• Products can be both cosmetics and drugs – if two intended uses
• Examples: Antidandruf shampoo, antibacterial hand soap
• Must comply with requirements for either/both drugs and cosmetics
Advertising
• Since 1971, Regulated by the Federal Trade Commission (FTC)
• No requirement to submit advertising to FTC before use
• FTC has policy guides on advertising that must be consulted
• National Advertising Division (NAD) of the Better Business Bureau is
the investigative arm of the voluntary self-regulation program
• NAD casework includes
• competitive challenges from other advertisers
• self-monitoring traditional and new media
• Ensure all claim support data is available before advertising